This invention relates to a humectant and lubricant solution for ophthalmic use based on a glycogen polysaccharide.
It is known that the instillation of humectant and lubricant solutions into the eye is indicated in some circumstances. These solutions are all the more useful if they mimic the functions of natural tear fluid.
This type of humectant and lubricant solution has therefore been given the name of xe2x80x9cartificial tearsxe2x80x9d, even when the capacity to mimic natural tear fluid is not entirely satisfactory.
Artificial tears are used, for example, to alleviate the symptoms of dry keratoconjunctivitis, exposure-induced keratopathies and other situations resulting in dry eye syndrome. In addition to this artificial tears are useful to wearers of contact lenses, particularly in the case of hard lenses.
One of the properties required from artificial tears is that they should produce a sensation of well-being and freshness which lasts for a sufficient length of time.
In the past it was considered that in order to achieve this objective artificial tears should have a high viscosity, and this was achieved by adding polymers such as cellulose esters, polyethylene glycol, polystyrene sulphonate or polyvinyl acid.
However, such artificial tears do not satisfactorily mimic the properties of natural tear fluid which, as is known, has a rather low viscosity (between 1 and 6 cP) [J. M. Tiffany, xe2x80x9cInternational Ophthalmologyxe2x80x9d, 15, 371-376, 1991 H. Botner, T. Waaler and O. Wik, xe2x80x9cDrug Development and Industrial Pharmacyxe2x80x9d, 16(5), 755-768, 1990].
In addition to this it has been shown that a viscosity greater than 20 cP is generally regarded as being uncomfortable on account of eyelid movement (J. I. Greaves, O. Olejnik and C. G. Wilson, xe2x80x9cPharma. Sciencesxe2x80x9d, 2(1 13-33, 1992). Also, viscosities in excess of 40-50 cP can cause occlusion of the tear duct and give the patient a continual sensation of having a foreign body in the eye (M. Amorosa, xe2x80x9cPrincipi di Tecnica Farmaceuticaxe2x80x9d, (Principles of pharmaceutical technology), 399, 1983).
U.S. Pat. No. 4,039,662 proposes that this disadvantage should be overcome through a low viscosity ophthalmic solution containing dextran or arabinogalactan together with benzylalkonium chloride. In particular, the abovementioned patent specifies that the polysaccharide component alone without benzylalkonium chloride is incapable of remaining adsorbed onto the cornea for a sufficiently long period (column 3, lines 9-13). In explanation of this behaviour it is hypothesised that the polysaccharide particles described in the aforesaid patent combine in solution with the benzylalkonium chloride by electrostatic attraction. This seems to form a complex having an electron charge which causes the macromolecule to be adsorbed onto the surface of the cornea (column 3, lines 19-37).
Furthermore, it is known from the literature that aqueous solutions of dextran have an osmotic pressure which is much greater than that of natural tears (F. J. Holly and E. D. Esquivel xe2x80x9cColloid Osmotic Pressure of Artificial Tearsxe2x80x9d, Journal of Ocular Pharmacology, 1, 327-336, 1985). Despite the fact that this contrasts with the principle according to which tho physical proportions of artificial tears should be as similar as possible to those of natural tears, Holly et al. specifically attribute the greater acceptance of dextran-based artificial tears by patients to the said greater oncotic pressure.
Now it has been surprisingly found that glycogen polysaccharides provide an ophthalmic solution of low viscosity and low oncotic pressure and exert a pleasing refreshing, lubricating and humectant effect on the cornea even in the absence of benzylalkonium chloride (Table I).
Therefore, it is an object of this invention to provide the use of a glycogen polysaccharide, as an active ingredient, substantially free of nitrogen when determined by the Kjeldahl method, for the manufacture of ophthalmic sterile aqueous solution useful as an artificial tear.
Preferably the glycogen polysaccharide Is prepared according to patent EP-B-0 654 048.
It has also been found that, in addition to being characterized by a long residence time In the eye, aqueous solutions of glycogen polysaccharides can be filtered to 0.2 microns, and can thus provide sterile solutions up to a concentration of 12% (w/v). In addition to this, these solutions have a low viscosity and a low oncotic pressure.
Typically the quantity of glycogen polysaccharide in the ophthalmic solution according to this invention is of from 0.1 to 12% (w/v).
Preferably it is of from 1 to 6% (w/v). Even more preferably it is of from 2 to 4% (w/v).
Typically the ophthalmic solution according to this invention has a viscosity of between 1 and 9 cP. Preferably it has a viscosity between 2 and 7 cP. Even more preferably, it has a viscosity between 2 and 6 cP.
Typically, the ophthalmic solution according to this Invention has an oncotic pressure of less than 5 mmHg. Preferably it has an oncotic pressure of less than 3 mmHg.
The ophthalmic solution according to this Invention may also contain other conventional ingredients such as: antioxidants, buffers, compounds to render the solution isotonic with tear fluid, stabilising agents, colouring agents and the like.
Typical examples of antioxidants are cysteine, ascorbic acid and taurine. The latter is also particularly preferred on account of its anti-free radical properties.
The quantity of antioxidant in the ophthalmic solution according to this invention will vary widely according to the preselected composition. In the specific case of taurine, the quantity is preferably of from 0.1 to 0.6% (w/v) and, even more preferably, from 0.2 to 0.4% (w/v).
Typical examples of buffers are borate, bicarbonate, acetate and phosphate buffers, and their quantities will be selected so as to regulate the pH of the ophthalmic solution according to this invention between 5 and 8. Preferably the buffer will be a phosphate buffer and the pH of the ophthalmic solution according to the invention will be adjusted between 6.5 and 7.5.
Typical examples of compounds suitable for ensuring that the ophthalmic solution according to this invention is isotonic with natural tear fluid are glycerine, sodium chloride and mannitol.
The quantities of these in the ophthalmic solution according to this invention will vary widely according to the preselected composition. In the particular case of mannitol, the quantity is preferably of from 0.5 to 3% (w/v). Even more preferably it is of from 1.5% to 2% (w/v).
The composition according to this invention may also contain one or more preservatives selected from the group comprising benzylalkonium chloride, thimerosal, methyl parabenes, ethyl parabenes, propyl parabenes and butyl parabenes.
The glycogen polysaccharide used in the examples below was extracted from Mytilus edulis or Mytilus gallus provincialis using the method described in EP-B-0 654 048 and had the following characteristics:
C: 44.44%
N: absent(1) 
reducing sugars(2): absent
[xcex1]D20: 198xc2x11.0 (c=1, water)
mean surface tension(3):
3% aqueous solution at 25xc2x0 C.: 66.29 mN/m
6% aqueous solution at 25xc2x0 C.: 61.04 mN/m
3% aqueous solution at 37xc2x0 C.: 59.19 mN/m
6% aqueous solution at 7xc2x0 C.: 58.20 mN/m
contact angle with glass(4) at ambient temperature (the comparison test with water yielded a result of 42xc2x0):
3% aqueous solution: 32xc2x0
6% aqueous solution: 18xc2x0.
Notes:
(1) determined by the Kjeldahl method,
(2) determined in accordance with F. D. Snell and Snell, xe2x80x9cColorimetric Method of Analysisxe2x80x9d N.Y., 1954, Vol. III, pag. 204,
(3)determined using a Lauda tensiometer,
(4)determined using a contact angle measuring device of the Face Contact Angle Meter, Kyowa Kaimenkagaki Co. Ltd., Nordtest type.